astro refresher pediatric malignancies malignancies 2013 ... review for management of pediatric...
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ASTRO REFRESHER Pediatric Malignancies
2013Shannon MacDonald
Conflicts
No Conflicts
Overview
Review for Management of Pediatric Malignancies
Overview for each site
Work up, treatment & RT guidelines
Appropriate RT modalities
what you need to know to manage and treat a patient
Pediatric Malignancies
CNS Tumors
Medulloblastoma/SPNET
Ependymoma
ATRT
Low Grade Glioma
High Grade Glioma
DIPG
Craniopharyngioma
Germ Cell Tumors
Non-CNS
Hodgkin’s Disease
Wilm’s Tumor
Neuroblastoma
Rhabdomyosarcoma
Ewing’s Sarcoma
Osteosarcoma
Sarcoma (other)
Retinoblastoma
Leukemia
Langherhan’s
Clinical Case
5 y/o boy presents with HA
For oral boards
Always safe to start with H & P with detailed exam of organs affected by specific malignancy
HA, n/v, cranial nerve deficits (double vision, facial droop, etc.), torticollis, back pain, neuropathy, neuro exam
Almost all children with a brain tumor will have a finding on neuro exam in addition to HA
CT or MRI brain should be ordered
Describe Images; Top 4 in differential
Differential Posterior Fossa Mass
Pilocytic Astrocytoma
Medulloblastoma
Ependymoma
ATRT (Atypical Teratoid Rhabdoid Tumor)
Frozen Path Medullo
Most of the tumor is easily removed. There is a thin carpet on the brainstem measuring 5 mm by 1 mm. Removal carries risk of brainstem injuring
How do you want to proceed? What amount of disease has been shown to increase the risk of recurrence?
What additional work up is required?
Medulloblastoma
Goal for medulloblastoma is to achieve less than 1.5 cm2 residual tumor
Additional work up includes
post-operative MRI (within 48 hours of surgery)
MRI spine (10-14 days post-surgery)
CSF (10-14 days post-surgery)
Ok to get MRI spine at diagnosis before surgery, but NOT CSF (why?)
Standard versus High Risk
Standard Risk
Not metastatic
<
1.5 cm2 residual
>
3 yrs. old
High Risk
Any of these factors
Is there a subgroup of “standard risk”
patients that are no longer
eligible for COG standard risk protocol?
Standard risk Medulloblastoma: prognostic impact of anaplasia in localized disease
Packer et al, JCO 2006
CCG-A9961N = 379 pts.
Anaplasia in 15% of pts.(diffuse or focal)
Excessive Anaplasia:EFS =
73% at 5 yr.
No Anaplasia:EFS =
83% at 5 yr.
Note: Large Cell/Anaplasia no longer allowed on SR COG Study
Staging of Medulloblastoma-
Chang (pre-MRI and even pre-CT era)
T1 –
tumor < 3 cm in diameter
T2 –
tumor >
3 cm in diameter
T3a extension into aqueduct of foramen
T3b invasion of brain stem (generally defined by intraoperative demonstration)
T4 midbrain, 3rd
ventricle or upper cord involved
M0 no metastasis
M1 microscopic CSF involvement
M2 gross seeding of 3rd ventricle
M3 gross seeding of cord
M4 extra-CNS metastases (esp. bone marrow, bone)
Standard Risk Medulloblatoma
CSI within 31 days of surgery to a dose of 23.4 Gy f/b posterior fossa (or involved field*) boost
Is this patient eligible for protocol?
ACNS0331
Randomizes children <8 to 18 CSI versus 23.4 CSI
Second randomization for all patients involved field versus whole posterior fossa
Weekly Vincristine during radiation
Cisplatin based chemotherapy after RT
Children’s Oncology Group
Average Risk Medulloblastoma ACNS0331 Schema
Age 3-7 years
Age 8-21 years
CSRT 18Gy(PF 23.4Gy)
CSRT 23.4Gy
CSRTCSRT 23.4GyPF boost 54Gy
IF boost 54Gy
PF boost 54Gy
IF boost 54Gy
PF boost 54Gy
IF boost 54Gy
R
R
R
R
Weekly vincristine during XRT
Chemotherapy
Weekly Vincristine f/b 8 cycles of Vincristine, Cisplatin, CCNU
Or Alternating AAB,AAB,AAB
Posterior Fossa Syndrome
Swallowing dysfunction
Ataxia
Mutism
Emotional Labiality
(SAME)
Does this change your management?
Treatment Planning
Simulation and Planning
CSI
Involved Field and Posterior Fossa
CSI
Pt. placed prone with prone mask on.
Spine: Plan first
Inferior: bottom of thecal sac +margin (determined from MRI, about S2)
Superior: C5-6 ( or as low as possible while still clearing shoulders on WB, so that when you feather up you won’t go through brain or mouth (photons)-for protons helps with dose distribution but exit is not an issue)
Lateral: about 1 cm lateral to vertebral body and to catch sacral nerve roots inferiorly field may be wider
CSI
Then WBRT set up
2 angles
1) Rotate the collimator to match the divergence of the spine field. {arctan (L/2)/SSD}
2)Kick the couch TOWARD beam to avoid divergence of the WBRT field into the spine field. {arctan (L/2)/SAD}
Also, angle WB gantry to avoid contralateral retina/lens, i.e.: RAO/LAO (for protons this is different RPO/LPO)
CSI
If spine field is too long, do extended distance. If field is still too long, split spine field into two, but leave a gap at cord and feather jxn weekly . Gap calculation usually around 3mm.
Feather all matches weekly (every 9 Gy)
*Collimate brain field to match divergence from spine field *For photons, use RAO and LAO to avoid divergence of brain
field into contralateral retina
Kick couch (feet towards gantry of brain field being treated)
Small hot spot if no couch kick
26
Neck match line
Matching thedivergence
27
Spinal cord match line
Matching depth
superiormidinferior
28
Spinal cord match linesuperiormidinferior
Matching depth
29
Spinal cord match line
Matching depth
superiormidinferior
RAO/LAO (photons)
Cribiform Plate
CSI Protons
PF and IF
Posterior Fossa -
C1 (inferior) to tentorium (superior) to
bones of occiput and temporal bones (lateral). THIS IS A CTV.
PTV 3 to 5 mm margin; should extend to posterior clinoid and C1/C2
95% of volume should receive prescription dose and no portion should receive less than 50 Gy
Involved Field-
gross tumor + resection cavity + 1.5 cm
margin (excluding bone and tentorium)
57 54 45 4239 36 30
Protons IMRTGy
IJROBP; 58; 3; 2004
Medulloblastoma; Posterior Fossa
Critical Structures
For oral boards, be able to find these critical structures on CT/MRI
Cochlea
Pituitary gland
Hypothalamus
Brainstem
Spinal cord
Side Effects
Nausea, vomiting, fatigue, skin irritation
Diminished bone growth
Infertility
Gastrointestinal distress
Second cancers
Neurocognitive deficits
Hearing loss
Pituitary axis dysfunction
Hypothyroidism
Cardiac dysfunction
Restrictive pulmonary disease
What is the treatment for High Risk Medulloblatoma or SPNET?
High Risk
36 Gy f/b boost to 54 Gy (IF or whole PF)
For spinal mets 45 Gy
Supratentorial PNET is treated just like High Risk Medulloblastoma and these patients are eligible for High Risk COG Trial
**Babies (< 3) although HR are tx with chemo first f/b RT (usually IF RT)
Children’s Oncology Group Other Than Average Risk (High) Medulloblastoma
ACNS0332 Schema
Age 3-21 years
Concurrent vcr & carboplatinwith RT
Concurrent vcrwith RT
CT alone
CT + isotretinoin
CT alone
CT + isotretinoin
R
R
R
•
1st
randomization: +/‐daily carboplatin 35 mg/m2/day for 30 doses over 6 ½
weeks and all get weekly vincristine 1.5 mg/m2 for a total of 6 doses.
•
CT with cisplatin, vincristine, and cyclophosphamide in 28 day cycles for a total of
6 cycles. (Cumulative cisplatin dose possible 450 mg/m2)
•
2nd
randomization to +/‐
Isotretinoin (80 mg/m2 twice daily on Day 1 and Days 16‐
28 in 28 day intervals during chemotherapy and days 15‐28 after chemotherapy
for a total of 12 cycles.)
Outcomes
Standard Risk Medulloblastoma
5 year EFS 83% no anaplasia 73% anaplasia
High Risk Medulloblastoma
5 year EFS 67%
Supratentorial PNET
5 year EFS 68%
Baby Medulloblastoma
5 year EFS approximately 50%
Packer, JCO 2006Chintagumpala, Neuro-Oncology 2009;1:33-40
ATRT
Recognized as a distinct entity since discovery of INI-1 tumor suppressor gene (loss of INI-1 indicates ATRT)
Usually occur in very young children
Poor prognosis but curable when disease is localized
Localized disease is treated with high dose chemotherapy followed by IFRT to 50.4 Gy
CSI for localized or metastatic disease and if child is over 3
Ependymoma
Ependymoma
Median age 5-6 years
2/3rds
are infratentorial; 1/3rd
supratentorial
Prognostic Factors
GTR!!!
Maximal surgical resection is very important for this disease
Histology
Work up is the same as medulloblastoma
Ependymoma
RT involved field to 54 –
59.4 Gy **
If metastatic disease on spine MRI or CSF 36 Gy CSI for children > 3 years
Chemotherapy on protocol but not proven to provide benefit for localized disease
Outcomes-
Close to 80% for GTR; 30-40% for STR
* Our standard is 54-55.8 Gy because of brainstem tolerance; COG protocols use 59.4 and other institutions use 59.4 Gy
Involved Field to 54 Gy
Protons IMRT
Involved Field
Protons IMRT
Best Available Published Data
153 patients with localized disease treated with 3D conformal
photon therapy
7 yr. LC 87%; EFS 69% and OS 81%
7 yr.
EFS grade II/III: 79% and 61%
7 yr. EFS GTR v STR: 77% v. 34%
7 yr. OS GTR v STR: 88% vs. 52%
Merchant et al, Lancet Oncology 10:258, 2009
Best Available Published Data
Very high rate of GTR (81.7%)
Complications
3 pts. with brainstem necrosis, steroids/HBO, 1 died, other
impaired (9 and 12 months from RT) (2.5%, S+RT)
4 cases cervical subluxation (all had laminectomies)
7 yr. CI of 2nd
malignancy: 4.1 % (n=4, 3 gliomas, 1 thyroid)
1 Moya‐moya (12 months after RT, age 1 at RT)
Merchant et al, Lancet Oncology 10:258, 2009
Proton Data
70 patients with localized disease treated with involved field proton therapy
3-year local control (LC), progression free (PFS), and overall survival (OS) was 83%, 76% and 95%, respectively
STR was significantly associated with worse PFS (54% versus 88%; p=0·001) and OS (90% vs.. 97% for GTR; p=0·001).
MacDonald, et al
PFS by histology and GTR
Patterns of Failure
•
We are seeing less local failures
•
Proportionally more distal failures but no increase in absolute # of distal failures
*
*
T12
L2
S2
GTR, Classic
GTR, Anaplastic
STR/NTR, Classic
STR/NTR, Anaplastic
Synchronous PF Failure*
COG ACNS 0121-
Closed
Ependymoma COG ACNS 0121
3 main groups for this study
Supratentorial non-anaplastic
Observation arm (no RT)
GTR
Received RT only to recommended dose of 59.4 Gy
STR
Received 7 weeks of chemotherapy f/b second look surgery if feasible
Anticipating publication in near future; this will represent largest Ependymoma study (280 patients)
ACNS 0831
Low Grade Gliomas
Most common pediatric brain tumor
Many (cerebellum, cerebral hemispheres) can be completely resected with 90% DFS without any additional therapy
LGG of the optic chiasm, hypothalamus, thalamus, tectum, and brainstem often cannot be completely resected and radiation or chemotherapy recommended
Juvenile Pilocytic Astrocytoma
c
Diffuse Fibrillary Astrocytoma
Histology
Optic/Hypothalamic
a b c
LGG of Tectum
Tx Recommendations
Biopsy for some sites if safe (usually no biopsy for optic glioma or tectal glioma), surgery or shunt/3rd
ventriculostomy to relieve symptoms or hydrocephalus
Radiation Therapy 45-54 Gy; usually 50.4 -54 Gy
Chemotherapy to delay radiation therapy (reasonable under the age of 10; preferred under the age of 5 and for kids with NF1; should always be discussed in multidisciplinary setting)
Chemotherapy
Delay SE’s of RT
Endocrine
Vasculopathy
moya-moya
Cognitive impairment
Second malignancy
Children with NF
Rarely prevent need for RT so use in patients where a delay is of benefit
Carboplatin & Vincristine most common 1st
line regimen
Radiation
Radiation
Effective and definitive
Most patients will ultimately require RT
New techniques; less toxicity
Permanent vision loss & endocrine deficits if chemo is ineffective and tumor grows
If older, chemotherapy is less likely to be effective
For optic/hypothalamic, if endocrine deficits at presentation less to lose
ACNS 0221 LGG study
Eligibility: pts. 3‐21 years with progressive LGG, pts. <10
must have had 1 or more chemotherapy trial.
Primary objectives: to measure the PFS and OS of patients
treated with conformal radiotherapy to 54 Gy.
RT guidelines:
GTV: all visible tumor on MRI (T1Gad and T2/Flair)
CTV: 5 mm margin
PTV: 3‐5 mm
Third Ventriculostomy
Procedure to relieve hydrocephalus
Creates flow from 3rd
ventricle to pre-pontine space
Other option –
shunt
a b
Protons 50.4
IMRT 50.4
What changes can you see on imaging 6-12 months later?
Tectal Glioma: Radiation treatment effect
Post Radiation Images:
Pre Radiation Images:
Diagnosis? Do you biopsy?
6 y/o boy presents with 1 week of ataxia, slurred speech, and double vision (6th nerve palsy apparent on exam: asymptomatic prior to this)
Diffuse Infiltrating Brain Stem Glioma
No need for biopsy
Regardless of path DIBSG prognosis is poor
Only biopsy if looks atypical or does not look like DIBSG-
i.e. dorsally exophytic
54 Gy RT to tumor + small margin
Tumors promptly response in 70% + --ssx improve
Response is not durable and most will recur in 6-12 months
Median OS 1 year
Many protocols investigating useful chemotherapeutic agents but no clear benefit
High Grade Gliomas Treatment
Standard of care includes maximal safe resection
and RT
Chemotherapy usually included but unclear benefit
3 yr. EFS for AA and GBM is 13% and 7% (Cohen, Neuro‐Onc 13:317, 2011)
Apparently worse than CCG 945, 5 yr. EFS 33% and 5 yr.
OS 36% (Finlay, 1995)
Thought to be due to more stringent path diagnosis, 14%
in CCG 945 not truly HGG (LGG most common,
ependymoma second)
XRT/TMZ followed by TMZ + CCNU
2 yr. EFS: ACNS0423 = 24%ACNS0126 = 18%
2 yr. OS: ACNS0423 = 35%ACNS0126 = 29%
Jakacki, COG study progress report 2010
TMZ + CCNU
TMZ
TMZ + CCNU
TMZ
TMZ/CCNU compared to VCR/CCNU
TMZ + CCNU appears equivalent to VCR/CCNU/Prednisone
TMZ not as significant a player as in the adult population
High Grade Glioma RT
54 to 59.4 Gy depending on location
T2 flair with margin to 45 Gy
T1 post contrast to total 54-59.4 Gy
Adolescent Male with HA, impaired upward gaze
Germ Cell Tumors
3-5% of all primary CNS childhood tumors
120-200 cases/year in USA
<1% of primary adult CNS tumors
GCT symptoms
Suprasellar
Diabetes Incipidus
GH abn
Other hormonal abnormality
Visual deficit
Pineal
Hydrocephalus
Parinaud’s Syndrome
Do not react to light
Pseudo-Argyll Robertson pupil
Work up
MRI of the brain and spine with attention to the suprasellar and pineal regions
Serum and CSF HCG & AFP
Biopsy unless markers +
still a bit controversial
Procedures to relieve hydrocephalus if needed
Clinical categories of CNS germ cell tumors
Germinoma (60 +%)
HCG < 50 mIU/ml in serum and CSF (this is soon to change to < 100)
No elevation of AFP
Non-germinoma germ cell tumors(NGGCT) (40-%)
Embryonal carcinoma (βHCG + AFP)
Endodermal sinus tumor (yolk sac) (AFP)
Choriocarcinoma (βHCG)
Immature teratoma
Mature teratoma (1%)
Age at diagnosis
Peak incidence in the 2nd and 3rd decades
Very rare in early childhood
Sex predilection by site
Pineal: male predominance (>5/1)
Suprasellar: equal male/female ratio
Variable incidence by region and/or ethnicity
Western populations: 3%
Rickert C, Childs Nerv Sys 17:503, 2001
Japan and Far East: 10%
Nomura K, J Neurooncol 54:211, 2001
Site predilection
Midline sites (95%)
Pineal (45%)
Suprasellar (40%)
Multifocal –
pineal and suprasellar (10%)
Non-midline sites (5%)
Sagittal T1 post gadolinium contrast image showing 3rd
ventriculostomy defect
What additional info can you gain from this procedure?
Multifocal 5-10%
Multifocal Disease-
seen on MRI
OR one lesion symptomatic and the other site asymptomatic
ALSO look for decrease in size of pineal or infundibulum following chemo
Treatment expectations
Germinomas are malignant tumors that are very responsive to cytotoxic therapies.
Radiotherapy (RT)
Chemotherapy (CHT)
Germinomas are highly curable
NGGCT are not as responsive and have a poorer prognosis
Radiation Therapy
Historically, radiation therapy was a diagnostic tool in the treatment of germinomas
Pineal region mass 20 Gy to a local field
Repeat head CT: if marked response, a diagnosis of germinoma was assumed
***We don’t do this anymore
For pure GCT
What are treatment options for localized disease
What are treatment options for disease that has spread to the spine?
RT for pure GCT
Highly curable tumor with radiotherapy alone
10 year survival with RT
85-95%
30-36 Gy to the CSI/WBRT/ventricles
45-50 Gy to the primary tumor
MOST STANDARD ANSWER FOR RT ALONE FOR LOCALIZED DISEASE
Whole vent to 24 Gy f/b boost to 45 GY
MOST STANDARD FOR DISSEMINATED RT ALONE
CSI to 24 Gy f/b boost to 45 Gy
RT + Chemo for pure GCT
MOST STANDARD for localized
2-4 cycles of carbo/etoposide or plantinum based chemo f/b 21 Gy WVRT f/b boost to 30 Gy (if CR to chemo)
*** do not use IFRT after chemotherapy b/c of reports of high rates of ventricular relapse
MOST STANDARD for disseminated
Same chemo f/b 21 Gy CSI f/b boost to 30 Gy
Alapetite, C. et al. NEURO ONCOL 2010 0:noq093v1-93; doi:10.1093/neuonc/noq093
Ventricular relapses after chemotherapy and IFRT
Protons
Lateral, 3rd, 4th ventricle, +/- pre-pontine cistern; go over this volume with your radiologist!! Atlas available on QARC website
Always draw your involved field volume at the same time and be sure it is included in WV volume!!
Outcome after radiotherapy alone
10-year overall survival in most series exceeds >85-
90%.
Late effects
in children are the primary concern in long
term survivors.
Neurocognitive
Endocrine
Second malignant neoplasms
NGGCT
Always chemo + RT (RT alone OS 20-45%)
For now, Cisplatin based chemotherapy and CSI (36 Gy f/b involved field boost to 54 Gy)
MOST COMMON REGIMEN
6 CYCLES ALTERNATING CARB/ETOP AND IFOS/ETOP
Last ACNS protocol indicates approx 85% OS with this regimen (failure to achieve CR poor PF)
Next ACNS will use same chemo with similar RT doses but change in RT volume to WVRT f/b boost
ACNS1123
Current COG Trial For Localized GCT & NGGCT
ACNS1123Combines NGGCT and pure GCT (2 strata)
Primary objectives:
1
To determine, as measured by 3 year PFS if volume/dose of RT can be reduced for NGGCT and if chemotherapy f/b low dose WVRT plus IF RT is effective for pure GCT.
2
To prospectively evaluate the cognitive, social, and behavioral functioning of children and young adults who are treated with reduced RT dose/volume
EligibilityStratum 1 (NGGCT)
Patients with identified levels:
Serum and/or CSF ß-HCG >100 mIU/mL, or,
Any elevation of serum and CSF AFP > 10 ng/mL, or greater than the institutional normal, irrespective of biopsy results.
Patients with any of the following elements on biopsy/resection,
irrespective of serum and/or CSF ß-HCG and AFP levels:
endodermal sinus tumor (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma, mixed GCT with malignant GCT elements.
Eligibility
Stratum 2 (Germinoma)
Patients with institutional normal AFP andß-HCG 5 -
≤
50 mIU/mL in serum and/or CSF are eligible.
Patients with bifocal involvement or pineal lesion with DI and ß-
HCG ≤
100 mIU/mL and institutional normal AFP in serum/CSF are eligible.
Patients with histologically confirmed germinoma or germinoma mixed with mature teratoma and ß-HCG ≤
100 mIU/mL and institutional normal AFP in serum/CSF are eligible.
ACNS1123-
NGGCT
Radiation Volume/Dose Question
Chemotherapy identical to ACNS0122
Can dose and volume of irradiation can be safely reduced to 30.6 Gy WVRT f/b IFRT to 54 Gy for patients achieving “complete response”?
36 Gy CSI f/b IF boost to 54 Gy 30.6 Gy WVRTf/b IF boost to 54 Gy
ACNS1123-
pure GCT
Chemotherapy
4 cycles of Carboplatin/Etoposide
Radiation
WVRT to 18 Gy
IFRT to bring primary disease to total 30 Gy
RT Guidelines
3D planning required
3D photons, IMRT, protons allowed
2 CTV’s
Whole Ventricles
Involved Field
IF CTV must be contoured upfront and added to whole ventricle volume to ensure full coverage
WVRT for all patients
While few patients were treated with WVRT on prior studies, all patients enrolled on ACN1123 will receive WVRT
Difficult volume to contour with variability among clinicians
Review of volumes from ACNS0232 demonstrated need for clear guidelines
ACNS1123 will allow for smaller margins and more conformal techniques
Whole ventricle atlas
To improve consistency
Provide a visual guide
Decrease protocol violations
Available on QARC website
Describe images (arrows): What do you think this is? What ssx might this child have?
Craniopharyngioma
Common presenting ssx
Visual
DI
Other endocrine
Increased ICP
How do you want to proceed?
Surgery
Surgical morbidity can be high in this region and it is rare that complete resection can allow for complete avoidance of RT
Surgical morbidity may include
DI
Hypothalamic obesity
Memory loss/personality change
Vision loss
Vasculopathy
What do you recommend post-partial resection?
Radiation
54 Gy (range 50.4-54 Gy) to tumor bed + 5 mm margin
What do you need to consider during RT?
Cystic component can change; may need to image during RT and adjust volumes
What is long term disease control?
90%
Craniopharyngioma
IMRT
What disease is likely?
What other ssx are likely? How do you want to proceed?
Retinoblastoma-
EUA
Work up includes EUA, MRI orbits and brain (r/o trilateral retinoblastoma;If extra ocular involvement or high risk features bone scan, bone marrow biopsy, and CSFNo pathology unless eye is removed
Vitreous Seeding
International Classification System for Retinoblastoma
Group A: Small tumors confined to retina not involving optic disc or fovea, < 3mm, at least 2DD from fovea and 1DD from optic nerve, no vitreous seeding or retinal detachmentGroup B: All remaining discrete tumors confined to the retina, no sub retinal or vitreous seeding, no retinal detachment > 5 mm from tumor base, no sub retinal fluid beyond 3 mm from tumorGroup C: Local sub retinal seeding or fine vitreous seeding <2DD from tumor, no retinal detachment > 5 mm from tumor base
International Classification System for RetinoblastomaGroup D: Diffuse disease with significant vitreous or sub retinal seeding or “snowballs”
or tumor masses , sub retinal
fluid involving up to total retinal detachment
Group E: Tumor touching lens, tumor anterior to anterior vitreous face involving ciliary body or anterior segment, diffuse infiltrating, neovascular glaucoma, opaque media from hemorrhage, tumor necrosis with aspetic orbital cellulitis, phthisis bulbi
For radiation we are usually treating Group C,D, E
Staging: Reese-Ellsworth Grouping
Group I:
Solitary or multiple tumors, < 4 disk diameters (DD), at or behind equator
Group II: Solitary tumors 4-10 DD, at or behind equator; or multiple tumors behind equator
Group III: Any lesion anterior to equator, Solitary tumors >10 DD behind the equator
Group IV: Multiple tumors, some >10 DD
Any lesion extending anteriorly to the ora serrata
Group V: Massive tumors involving more than half of the retina, Vitreous seeding (Group Vb)
Prognostic classification to predict vision preservation after EBRT
Genetics -
distribution
10% family history + 90% no family history
20-30% bilateral 70-80% unilateral
10% unilateral,heritable
60-70%Unilateral,Non-heritable
20-30%Bilateral,heritable
10% bilateral,Heritable
bilateral unilateral
heritable Non-heritable
Genetics
Two-hit hypothesis
Hereditary form: germline mutation exists in one allele
Single somatic mutation to second allele results in cancer
Random mutations to RB1 are relatively common in retinal cells
Sporadic form: no germline mutation
Requires somatic mutations to both copies of RB1 in the same retinal cell
Alfred Knudson: 1971 sentinel paper. Original question: How does one explain sucha tumor that can be either heritable or non-heritable?
Patterns of spread
Arises in the retina and proliferates rapidly
Endophytic or exophytic growth
May “seed”
the vitreous and fill the globe
Spreads along optic nerve toward brain
May extend outside the globe, into the orbit
Extra orbital spread in the CNS or bone marrow
Trilateral RB: involvement of the pineal gland
Rare (6%) hereditary form with poor prognosis
Treatment options
Enucleation
Exenteration
Local therapies:
Cryotherapy
Photocoagulation
Laser hyperthermia
Radioactive plaque therapy
External beam radiation therapy
Chemotherapy
Enucleation
Appropriate when little or no useful vision in the eye
Resect long segment of optic nerve
Avoid penetration of the globe; risk of tumor spill
Orbit growth is impaired
Good cosmesis with prosthesis
Used for 90% of unilateral tumors in U.S.
Exenteration
Removal of:
Globe
Extra ocular muscles
Lids
Nerves
Orbital fat
Indications: extensive tumor breaching the globe (F/U with EBRT and chemo)
Recurrence of tumor in the socket after enucleation
Chemotherapy
Goal is to delay or avoid EBRT
Focal therapies (cryotherapy, laser therapy, photocoagulation) are still required
Vincristine, carboplatin, etoposide x 6
CHOP regimen
Carboplatin alone
MSKCC regimen
EBRT
EBRT indications
Preservation of useful vision
Tumor within the macula
Tumor too extensive for focal therapy
Bilateral advanced intraocular disease
Salvage after failure of local therapy
Treatment of extra ocular or metastatic disease
** MOST COMMON SCENARIOS to use EBRT?
EBRT-Indications
1) VITREOUS SEEDING2) LARGER TUMOR IN MACULA–
CONSOLIDATION
POST CHEMO3) POST ENUCLEATION HR FEATURES (MOST COMMON POSITIVE OPTIC NERVE MARGIN
DOSE IS ALWAYS 45 Gy; Volume is 1) Posterior globe/nearly whole globe 2) tumor with generous margin 3) orbit with optic nerve up to chiasm
Retinoblastoma
Photons, 1984 Protons
Treatment Results
5 year survival is >90% in U.S.
Preservation of eye with EBRT
95% Stage I
50% Stage IV-V
Visual acuity is excellent in most patients (20/40)
Worse if macula involved
Blach et al IJROBP 35:45 1995Egbert et al Arch Ophthalmol 98: 1828, 1978
Complications
Cataract formation
Dry eye
Uncommon if conjunctiva and lacrimal glands spared
Retinopathy
Low risk with doses < 45 Gy
Bone growth abnormalities
Occur with EBRT or nucleation
Second cancers
Increased risk with germline RB mutation
Increased risk regardless of RT
Higher risk in RT field
Higher mortality for in-field sarcomas
Sarcomas most common (bone and soft tissue)
Higher mortality from 2nd
tumors than RB in U.S.
Second cancers
NY & MA: 1604 patients from 1914-1984
Hereditary RB:
RR = 30
Cumulative incidence 51% at 50 years
Radiation dose response for sarcomas (rate drops to 27% for patients not receiving radiation therapy).
Nonhereditary RB:
Cumulative incidence 5% at 50 years
Wong et al JAMA 278: 1284, 1997
2 y/o with abdominal pain, fever, hematuria
What is your differential diagnosis?
Wilm’s Tumor and Neuroblastoma
Wilm’s Tumor
Most common abdominal malignancy of childhood
Children usually present with painless abdominal mass
Work up includes US abdomen to start, CT abdomen, Chest CT
Surgery upfront (US standard)
For Rhabdoid histology add bone scan and MRI brain
For Clear Cell, add bone scan
Wilm’s Tumor
Staging
Stage I: tumor limited to capsule and completely resected
Stage II: Tumor beyond kidney and completely resected
Beyond kidney includes
Penetrates Renal capsule
Lymphatics or veins of Renal sinus
Tumor in Renal vein
Stage I and II-
resection with negative margins; no LN
Wilm’s Tumor
Staging
Stage III: SLURPP
Spillage (localized and diffuse)
Lymph Nodes
Unresectable
Residual
Peritoneal implants
Prior biopsy** changes since NWTS-5-
localized spillage and biopsy
now stage III (before Stage II)***SLURPP is important to remember for indications for RT
for FH Wilm’s
Wilm’s Tumor
Staging
Stage IV: Hematogenous Mets or spread beyond abdomen
Stage V: bilateral disease
Histology
Favorable Histology
Focal Anaplasia
Diffuse Anaplasia
Clear Cell Sarcoma of the Kidney
Rhabdoid tumor of the Kidney
Epidemiology
Associated with clinical syndromes
WAGR (Wilms’
Tumor, aniridia, genitourinary
malformations, mental retardation) WT1 –
11p13
Denys-Drash syndrome
(pseudohermaphroditism,
mesangial sclerosis, renal failure, Wilms’
Tumor)- also WT1
Beckwith-Wiedmann syndrome
(gigantism,
omphalocele, macroglossia, genitourinary abnormalities, ear creases, hypoglycemia, hemihypertrophy, Wilms’
Tumor) “WT2”
–
11p15
WT1 - tumor suppressor
RT
No RT for FH Stage I or II
RT for ALL focal and diffuse anaplasia, CCSK, Rhabdoid
Flank to 10.8 Stage III FH, Stage I-III focal anaplasia, Stage I-II diffuse anaplasia, Stage I-III CCSK; Flank to 19.8 Gy for Stage III DA
10.8 boost to any residual
WART to 10.5 Gy for +cytology, tumor spill, peritoneal seeding, prior biopsy (indications that put whole abdomen at risk*)
RT
WLI 10.5 Gy (< 12 mo.) and 12 Gy > 12 mo.
Whole brain 21.6 Gy
Liver focal-
19.8 Gy
Bone mets 25.2 Gy < 16 years; 30.6 Gy > 16 years
LN RT resected 10.8 Gy; not resected 19.8 Gy
Chemo for Wilm’s
VAA-
Vincristine, Actinomycin D, Adriamycin
(occasionally only VA for FH early stage)
CAVE for Clear Cell –
Cytoxan, Adriamycin, Vincristine,
Etoposide
CEC for Rhabdoid –
Carboplatin, Etoposide, Cytoxan
Neuroblastoma
Variable prognosis
4th
most common malignancy
Most common malignancy in children < 18 months
Tumor of neural crest tissue/sympathetic nervous system chain
Clinical Presentation
Abdominal mass with organ compression (children less well than Wilm’s typically)
Metastases common and systemic symptoms common (pain, fever, refusal to walk)
Neck mass (Horner’s Syndrome)
Spinal cord compression
Respiratory compromise :Pepper Syndrome (caused by liver mets)
Rare
Intractable diarrhea (VIP)
Opsoclonus-myoclonus-truncal ataxia (paraneoplatic)
Blueberry muffin sign
Skull mets (orbital ecchymosis)
Work up?
CT and/or MRI of primary site
Bone marrow biopsy
MIBG scan
Chest/Abdomen/Pelvis CT for metastatic disease
Urine catecholamine's (VMA and HVA)
Staging INSS
1-
localized and completely resected N0
2A-
localized and incompletely resected N0
2B-localized (complete or incomplete resection) + ipsi LN
3-
unresectable unilateral and crossing midline +/-
LN;
unilateral tumor with contra + LN
Staging INSS
4-
distant mets
4S-
localized primary tumor (1, 2, 2A) in patient < 1
year old with skin, liver, bone marrow involvement
Prognostic Factors
Age (>1, >18 months)
MYCN amplification
LOH 1p or 11q
Shimada histology (UF)
Hyperdiploid better than diploid
ANBL0532
High Risk Neuroblastoma
Phase III examining role of intensified consolidation chemotherapy, use of new drugs during induction, and local RT
Randomizes to 1 or 2 transplants
High Risk
Patients with newly diagnosed neuroblastoma with INSS Stage 4 are eligible with the following:
a. MYCN amplification, regardless
of age or additional biologic features.
> 18 months (>547 days) regardless of biologic features.
Age 12 –
18 months (365-547 days) with any of the
following three
unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index = 1) or any biologic feature that is indeterminate/unsatisfactory/unknown.
Patients with newly diagnosed neuroblastoma with INSS Stage 3 are eligible with the following:
MYCN, regardless of age or additional biologic features
Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status
Patients with newly diagnosed INSS Stage 2a/2b
with MYCN amplification, regardless of age or additional biologic features
4S with N-Myc amplification
RT-Neuroblastoma
Primary site post induction chemo volume(PRIOR to surgery)
21.6 Gy
Residual Disease
Additional 14.4 Gy (to total 36 Gy) (after surgery and induction chemo)
Metastatic Disease (if persistent after cycle 6 of induction)
21.6 Gy
@ 1.8 Gy per fraction
Neuroblastoma
Organs at Risk
Liver
No > 50% of liver > 900 cGy
No > 25% of liver > 1800 cGy
Neuroblastoma
Organs at Risk
Kidney
If well lateralized, ipsilateral kidney may receive 1440 cGy; 50% may receive 1980 cGy; for contralateral 50% may receive 800 cGy; no more than 20% should receive 1200 cGy
If not well lateralized, both kidneys may receive a mean dose of 1440 cGy and no > 50% receive 1980 cGy
What is tx of 4S with respiratory compromise?
Can try chemo first
For RT, 1.5 Gy x 3 to liver
Rhabdomyosarcoma
RMS: Work up
Hx and PE
CT and MRI of primary site
Biopsy
Chest/Abdomen CT
RMS: Work up
BMBx
Bone scan
(PET is very helpful! Need to get prior to CT to be helpful though)
If parameningeal, then CSF cytology and brain MRI
RMS Primary site is prognostic•
Favorable sites: •
Head/neck (non parameningeal)
•
Orbit•
GU (non bladder/prostate)
•
Biliary tract
•
Unfavorable sites: •
Parameningeal
•
Bladder/prostate•
Extremities
•
Other: Trunk/retroperitoneum
RMS: Clinical GroupsGroup Extent of disease/surgical result
I A Localized tumor, confined to site of origin, completely resected
B Localized tumor, infiltrating beyond site of origin, completely resected
II
Micro
+
A Localized tumor, gross total resection, but with microscopic residual
disease
B Locally extensive tumor (spread to regional lymph nodes), completely
resected
C Locally extensive tumor (spread to regional lymph nodes), gross total
resection, but microscopic residual disease
III
Gross
dz
A Localized or locally extensive tumor, gross residual disease after biopsy
only
B Localized or locally extensive tumor, gross residual disease after major
resection ( 50% debulking)
IV
metsAny size primary tumor, with or without regional lymph node involvement,
with distant metastases, irrespective of surgical approach to primary tumor
StagingStage Sites Invasiveness Size N M
1 Fav site Orbit
Head and neck*
GU (non‐bladder/prostate)
Biliary tract
T1 or T2 a or b Any N M0
2 Unfav
site, N0,
small
Bladder/prostate
Extremity
Cranial parameningeal
Other
T1 or T2 a N0 or Nx M0
3 Unfav
site, Big or
node +
Bladder/prostate
Extremity
Cranial parameningeal
Other
T1 or T2a N1 M0
b Any N M0
4 mets All T1 or T2 a or b N0 or N1 M1
T Stage N Stage M stage
T1: Confined to anatomic site of origin
T2: Extension
a: 5 cm in diameter
b: >5 cm in diameter
N0
: Not clinically involved
N1
: Clinically involved
NX
: Clinical status unknown
M0: No distant
metastases
M1: Distant metastases
present
Risk Stratification
Low risk: localized, embryonal, any resected site (group I/II)
AND favorable sites group III
Intermediate risk: any localized alveolar (group I‐III) or
embryonal unfavorable site (group III)
High risk: metastasis
RMS: RT Timing per open COG protocols
•
Low risk: week 13
•
Intermediate risk: week 4
•
High risk: week 20 (primary and some mets) unless emergent or ICE with PM RMS, which is
week 1) more mets can be treated at week 47)
Timing may change on the next COG RMS Protocols
RMS: RT Dose Guidelines•
0 Gy: Group I embryonal
•
36 Gy: Resected node negative disease (alveolar) and after
delayed primary resection of embryonal, or for group IIa (pos
margins); except low risk pts. (see below)
•
41.4 Gy: Resected node positive disease, (also Low risk pts.
with micro margins +; yes, counter‐intuitive)
•
45 Gy: dose for gross disease in orbit (may change for next
COG trial to 50.4 Gy)
•
50.4 Gy: dose for gross disease (non orbit)
Sarcomas of Bone
What are the 2 most common types of Bone tumors in children? What are classic Radiographic appearances?
Codman’s Triangle, Onion skin
Sunburst
Sarcomas
Osteosarcoma
Most common –
600 cases in US per year/3%
malignancies
Metaphyseal
Lytic destruction and new bone formation (“sunburst”); Codman’s triangle may be seen
Ewing’s
2nd
most common-
250 cases per year in US
Diaphyseal
Onion skin and Codman’s triangle
Osteosarcoma Staging
Technetium bone scan Chest CT
Osteosarcoma
Epidemiology
Peak incidence in 2nd
decade
20% have mets at dx
80% of mets are lung
20% involve bone
Osteosarc: sites of disease
Most common sites:
Distal femur (48%)
Proximal tibia
Proximal humerus
Pelvis
Bielack, JCO 2002
Prognostic Factors
Stage (localized vs.. metastatic)
Localized extremity lesions: 5 yr. EFS = 65 - 70%
Metastatic disease: 5 yr. EFS = 15 – 40%
Bone mets, bilat lung mets, > 4 lung nodules:
5 yr. EFS = 15-20%
Treatment
Surgery alone (amputation) until mid-70’s
Only 15-20% survival
> 80% of pts. died of recurrent, metastatic disease
Addition of chemotherapy in 1970’s – 1980’s
Active agents
Methotrexate
Doxorubicin
Cisplatinum
Ifosfamide
Must attempt to resect all identifiable sites
Role for XRT?
RT reserved for close/positive margins or inoperable sites
Skull base
Spine (?)
Pelvis (investigational)
Very limited published data re: local control with RT only
Dose > 60 Gy if feasible
Ewing’s
Small round blue cell
CD99 +, WNT –
Translocation 11:22-
EWS/FLI fusion protein (85-
90%) and 21:22
Cell of origin unknown
Ewing’s
Male predominance
May arise from soft tissue
Work-up
CT/MRI of primary
CXR, CT of chest
Bone Scan
Bone Marrow Biopsy
Labs (ESR/LDH)
Biopsy
PET at many institutions
Prognostic Factors
Metastasis
Location, distal better than proximal, failures 5% for distal, 25% for proximal, 35% for central
Size, < or equal to 8 cm better that > 8cm (failure rate of 10% v. 30%)
Elevated LDH
Age > 17 years (or <10, 10-17, >18)
Response to chemo-St Jude’s Study
Correlation of imaging response -
reduction of soft
tissue mass with chemo -
with outcome
Response to chemo:
5-y EFS 64% for CR
5-y EFS 13% for PR/NR
Tumor size:
< 8 cm, 90% LC
> 8 cm, 44% LC
Standard Chemo: VDC + IE
Grier et al, NEJM 2003Old Std chemo: VCR/Doxo/CTX/ActinoExper chemo: above alt with Ifos/Etop
Intensity of Chemo (q 2 wks vs. q 3 wks)
Intensive Regimen:VCR/Doxo/ CTXalt with Ifos/EtopCourses q 2 wks(previously q21 days)
COG study AEWS0031R Womer, PI:Intensive EFS = 75%Standard EFS = 65%
POG 8346
XRT alone:65% LC
No difference between whole bone and tailored field
Local control correlated with quality of XRT port:
80% for appropriate port
48% for minor deviation
16% for major deviation
Ewing’s
Primary tumor
45 Gy to pre-chemo tumor + 2 cm margin f/b CD to post-
chemo soft tissue but whole bone extent of involvement+ 2 cm margin to 55.8 Gy; try to spare strip of skin and joints if possible
Bone mets 45 Gy
Lung mets 15 Gy
What is you differential dx?
Langerhans's
LCH is accumulation or proliferation of clonal population of cells with phenotype of LCH cells
May affect skin, bone, lymph nodes, lungs, GI tract, CNS by causing DI
Syndromes
Letter-Siwe Disease
< 2 years
Splenomegaly, hepatomegaly, LAD, anemia, hemorrhagic diathesis
Poor prognosis
Hand-Schuler-Christian
> 2 years
Exophthalmos, lesions of skull/bone
DI
Good prognosis
Treatment
If asymptomatic, may be observed
Surgery (spontaneous regression following biopsy may be seen)
Steroids
Chemotherapy (controversial, topical for skin)
Radiation –
usually for symptomatic vertebral body
lesions, skull lesions, rare use for DI.
Dose 5-10 Gy in 3-5 fractions
Pediatric Hodgkin’s
Patients usually present with fever, night sweats, shortness of breath
Excisional lymph node biopsy for diagnosis
Avoid steroid administration prior to biopsy
Work up CT, PET/CT, labs including LDH, ESR, LFTs
B ssx or advanced disease-
consider bone marrow
biopsy
Staging
Stage I: Involvement of single lymph node region (I) or localized involvement of a single extra lymphatic organ or site (IE).
Stage II:Involvement of 2 or more lymph node regions on the same
side of the diaphragm (II) or localized contiguous involvement of a single extra lymphatic organ or site and its regional lymph node(s) with involvement of 1 or more lymph node regions on the same side of the diaphragm (IIE).
Stage III:Involvement of lymph node regions on both sides of the
diaphragm (III), which may also be accompanied by localized contiguous involvement of an extra lymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIIE+S).
Stage IV:Disseminated (multifocal) involvement of 1 or more extra lymphatic organs or tissues, with or without associated lymph node involvement, or isolated extra lymphatic organ involvement with distant (non-regional) nodal involvement.
Treatment
Multi-agent chemotherapy followed by involved field or involved nodal radiation
ABVD f/b 21 Gy IFRT most standard
Treatment evolving to be response based and trials exploring omission of radiation
Leukemia
Cranial RT to 12-
18 Gy (most give 12 Gy) at 1.8 Gy
per fraction or 1.5 Gy per fraction
T cell disease and high WBC (>50K)
CNS 3 (> 5 WBC/ul in CSF and blasts) –
usually 18 Gy
Age > 10
RT is considered as part of treatment for CNS recurrence (CSI 18 Gy; CrI 18-24 Gy) and testicular relapse/persistent testicular disease (20 Gy)
Almost finished!
What is your recommendation for a 2 y/o
M with anaplastic
ependymoma
of the 4th
ventricle s/p
GTR, negative CSF and spine MRI
A) CSI to 36 Gy
f/b
IF boost to 54 Gy
B) IFRT to 54 Gy
C)chemotherapy
for 6 months to delay radiation until
the child reaches the age of 3 years
D)Chemotherapy
alone and RT only for tumor
recurrence
E)Observation
B) IFRT to 54 Gy
Which of the below characteristics is NOT included in the traditional stratification for medulloblastoma
into standard or high-risk disease, but has been found to confer a less favorable prognosis?
A) age less than 3
B) + CSF
C) anaplastic
histology
D) Desmoplastic
histology
E) > 1.5 cm2
C) Anaplastic
histology
Which of the following regimens would NOT be acceptable for management of a localized pure
germinoma
of the pineal gland for a 17 y/o
Male?
A) 24 Gy
to the whole ventricles f/b
a boost to the
pineal gland to total 45 Gy
B) Carboplatinum/Etoposide
for 2-4 cycles f/b
21 Gy
to
the whole ventricles f/b
IFRT to the pineal gland
C) Carboplatinum/Etoposide
for 2-4 cycles f/b
IFRT to
30 Gy
D) Carboplatinum/Etoposide
for 4 cycles f/b
18 Gy
to
the whole ventricles f/b
boos to 30 Gy
on COG study
C) Carboplatinum/Etoposide
for 2-4 cycles f/b
IFRT to
30 Gy
Thank you!
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